Stability Profiles of Drug Products Extendedbeyond Labeled Expiration Dates
ROBBE C. LYON,1 JEB S. TAYLOR,1 DONNA A. PORTER,2 HULLAHALLI R. PRASANNA,1 AJAZ S. HUSSAIN3
1Division of Product Quality Research, Center for Drug Evaluation and Research, Food and Drug Administration,HFD-941, White Oak, Life Sciences Building 64, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993-0002
2Division of Field Science, Office of Regional Operations, Office of Regulatory Affairs, Food and Drug Administration,Rockville, Maryland 20857
3Vice President & Global Head of Biopharmaceutical Development, Sandoz, 506 Carnegie Center, Princeton,New Jersey 08540
Received 6 January 2006; accepted 17 March 2006
Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20636
ABSTRACT: The American Medical Association has questioned whether expirationdating markedly underestimates the actual shelf life of drug products. Results from theshelf life extension program (SLEP) have been evaluated to provide extensive data toaddress this issue. The SLEP has been administered by the Food and DrugAdministration for the United States Department of Defense (DOD) for 20 years. Thisprogram probably contains the most extensive source of pharmaceutical stability dataextant. This report summarizes extended stability profiles for 122 different drug products(3005 different lots). The drug products were categorized into five groups based onincidence of initial extension failures and termination failures (extended lot eventuallyfailed upon re-testing). Based on testing and stability assessment, 88% of the lots wereextended at least 1 year beyond their original expiration date for an average extension of66 months, but the additional stability period was highly variable. The SLEP datasupports the assertion that many drug products, if properly stored, can be extended pastthe expiration date. Due to the lot-to-lot variability, the stability and quality of extendeddrug products can only be assured by periodic testing and systematic evaluationof each lot. ß 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci95:1549–1560, 2006Keywords:
shelf life; drug stability; shelf life extension program; SLEP; expiration
than their labeled expiration dates and acknowl-edged that best evidence to support this resides in
The concern that expiration dating may markedly
the shelf life extension program (SLEP). Smaller
underestimate the actual shelf life of drug
studies have addressed the long-term stability of
products has been an issue.1–3 The American
drug products5,6 and drug substances.7 One study
Medical Association (AMA) recently reviewed the
determined that four products, captopril tablets,
procedures for setting pharmaceutical expiration
flucloxacillin capsules, cefoxitin injection, and
dates and the clinical and fiscal consequences of
theophylline tablets stored under ambient tem-
setting such dates.4 The AMA concluded that the
peratures maintained at least 98% of label claim
actual shelf lives of some products are greater
for drug content for 18–170 months past thelabeled expiration dates.5 In a modification to the
Correspondence to: Robbe C. Lyon (Telephone: 301-796-
0019; Fax: 301-796-9816; E-mail: robbe.lyon@fda.hhs.gov)
industry, the Food and Drug Administration
Journal of Pharmaceutical Sciences, Vol. 95, 1549–1560 (2006)ß 2006 Wiley-Liss, Inc. and the American Pharmacists Association
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 95, NO. 7, JULY 2006
(USP) were urged to determine the benefits and
valuable source of long-term stability data for a
risks associated with lengthening expiration
dates and to subsequently conduct longer stability
This report summarizes data for 3005 lots
testing. In response, all of the data from the SLEP
representing 122 drug products generated by the
was reviewed and analyzed. As a retrospective
SLEP since 1986. Based on stability assessment,
analysis, this report summarizes extended drug
88% of the lots were extended beyond their original
product stability data collected by the SLEP over
expiration date. Of the 2652 lots extended, only
18% were eventually terminated due to failure.
The International Conference on Harmoniza-
The rest of the lots are either still active (35%) or
tion (ICH) defines shelf life as ‘‘the time period
were abated (47%) by the military. The shelf life
which a drug product is expected to remain within
extension results were summarized in tabular
the approved shelf life specification, provided that
form. The products were arranged into groups
it is stored under conditions defined on the
container label.’’8 It is expected that the actualshelf life will slightly exceed the projected labeledshelf life. Pharmaceutical manufacturers are
required to assign an expiration date to each drugproduct marketed in the United States. The
labeled shelf life is estimated using appropriatestability testing (21 CFR 211.137 and 211.166)
The SLEP is a key component of the Medical
under current good manufacturing practices as
Readiness Strategic Plan as developed by the
established and monitored by the FDA. The
DOD Health Affairs and the Military Medical
stability assessments of both the new drug sub-
Departments. The DOD Defense Medical Stan-
stance and the new drug product stored under
dardization Board (DMSB) oversees the SLEP
controlled conditions are required documentation
program and acts as an interface between the
for submission to the FDA in a new drug applica-
military services and the FDA. Pharmaceutical
tion (NDA). The assessment follows scientifically
drug products sealed in original container clo-
based technical procedures as described in the ICH
sures are stored under controlled conditions by
Q1A(R2) Guidance.8 The initial expiration date is
the military services. Certain lots of drug product
based on the amount of real-time stability data
that are approaching their labeled expiration date
(generally from pilot scale batches) for the drug
are selected by the DMSB for participation in the
product available at the time of approval of the
SLEP program. Representative sealed containers
NDA. This initial date may later be extended
of drug product from a given lot are submitted to
contingent upon the receipt of acceptable support-
the FDA SLEP coordinator in the Office of
ing data from the manufacturer based on acceler-
Regulatory Affairs for testing by the FDA field
ated stability studies and actual real-time stability
labs. The test results are transmitted through the
data collected from the first three production
FDA SLEP coordinator to the FDA SLEP chemist
batches. Drug products marketed in the United
in the Division of Product Quality Research
States generally have a labeled shelf life of 12–
Research (CDER) for analysis. The FDA SLEP
The SLEP is administered by the FDA for the
chemist evaluates the test results, approves or
U.S. DOD9 and recently for the Strategic National
rejects the extension of the shelf life for that lot
Stockpile (SNS). To maintain a state of readiness,
and archives the data, evaluations, and approvals
the military maintains, under controlled condi-
for the program. Approval for a new expiration
tions, large stockpiles of pharmaceuticals sealed in
date for that lot of drug product is transmitted
their original container closures. A system of
through the FDA SLEP coordinator to represen-
extending the functional shelf life of these drug
products beyond their original expiration date wasinitiated to reduce the high cost of replacing these
stockpiles. Based on a comprehensive testingprogram, the shelf life of several drug products
Sealed containers of drug product from a given lot
has been extended on a lot-by-lot basis. This
are sent to an FDA field lab. Samples are
program has resulted in substantial savings to
subjected to a battery of tests prescribed by
the military. In return the FDA has access to a
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 95, NO. 7, JULY 2006
specifications are based on compendial (USP)
autoinjectors, the attributes were potency (assay),
product release tests or the product release tests
degradants, pH, preservatives, injection mecha-
as described in the original FDA submission
(NDA). If a lot fails any specification based onthe battery of tests, then the shelf life for that lotis expired.
The 122 drug products evaluated by this study
were categorized into five groups (see Tab. 1)
Extending the shelf life is based on developing a
based on shelf life extension data (relative
history of real-time stability data for each lot of
number of lots initially extended and number of
drug product. This data is compiled by continual
extended lots terminated). For the products
testing within the SLEP. Test results from each
assigned to Groups 1 and 2, all lots were extended
retest project form a set of real-time data. That
beyond their original expiration date. The pro-
real-time data is evaluated and an updated
ducts assigned to Groups 3, 4, and 5 had some lots
expiration period for that lot of drug product
that were denied initial extension. Overall, 2650
is predicted using regression analysis. Each
(88%) of the 3005 lots were extended past
retest attribute generates a particular remaining
their original expiration date for an average of
expiration period. If each remaining expiration
66 months. Of these, 934 lots (35%) are still
period predicted is longer than 1 year, the lot of
active and were granted an average extension of
drug product is granted a new expiration date. An
62 months, 1237 lots (47%) were abated before
‘‘initial extension failure’’ indicates that the lot
failure (dormant) after an average extension of
could not be extended past original expiration
70 months, and 479 lots (18%) were terminated
date. A ‘‘termination failure’’ indicates that a
due to failure after an average extension of
previously extended lot eventually fails upon re-
65 months. Of the 479 lots that eventually failed,
testing and based on regression analysis predic-
no lots failed before 1 year and 312 lots were
tions, cannot be extended for an additional year.
further divided into subclasses based on the
number of lots tested for each product. For
The attributes tested for a drug product varied
these products, none of the extended lots were
depending on the dosage form. For solid oral drug
terminated due to failure (periodic retest). Each of
products, the attributes were potency (assay),
the 15 products assigned to Group 1A (Tab. 2) had
impurities, water content, dissolution, and physi-
at least 10 lots evaluated. Of the 466 lots tested,
cal appearance. For reconstituted dry powders, the
284 lots (primarily 205 lots of ciprofloxacin tablets)
attributes were potency, pH, water content, and
are still active in the program and available for
physical appearance. For injectable solutions, the
use. The average extension for these active lots
attributes were potency, impurities, pH, preserva-
was 52 months. The remaining 182 lots were not
tives, and physical appearance (color, particu-
further tested or extended and are categorized as
lates). For creams and ointments, the attributes
dormant. The average extension for these dormant
were potency, pH, and physical appearance. For
lots was 67 months. The average extension time for
Number of Extended Average Extension Time
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 95, NO. 7, JULY 2006
Group 1A: Products With No Failures (10 Lots tested)
aSee ‘‘spray’’ dosage form (Group 5).
bSee ‘‘tablet’’ dosage form (Group 3).
cSee ‘‘autoinjector’’ (Group 2) and ‘‘injection-solution’’ (Group 3) dosage forms.
dSee ‘‘granules’’ dosage form (Group 1B).
eSee ‘‘injection-solution’’ dosage form (Group 2).
all of the lots from these 15 products was
are now dormant. The average extension for these
58 months, ranging from 12 to 184 months. The
dormant lots was 55 months, ranging from 12 to
mean extension times and the ranges of extension
114 months. The tablet dosage form of chlorpro-
times for the individual products are provided in
the table. For six of the products the extension
Each of the 20 products assigned to Group 2
times represent a combination of the active and
(Tab. 5) had some lots that could not be repeatedly
dormant lots. In these cases, the range for the
extended, one attribute eventually failing during
active lots is annotated in the table. Other dosage
periodic retest. Of the 254 lots tested, 41 lots
forms of diphenhydramine HCL, doxycycline
eventually failed and were terminated, 211 lots are
hyclate, morphine sulfate, potassium iodide, and
now dormant and 2 lots are currently active. For
sodium chloride were assigned to other groups.
the terminated lots, the amount of shelf life
The 25 products assigned to Group 1B (Tab. 3)
extension before the failure ranged from 12 to
had 5–9 lots evaluated. Of the 164 lots tested, 143
103 months with an average of 53 months.
lots are dormant and 21 lots are still active. The
Termination was due to a variety of test failures
average extension for the dormant lots was
as indicated in the table. The average extension for
61 months and for the active lots was 92 months.
the 211 dormant lots was 59 months ranging from
The average extension time for all of the lots from
15 to 137 months. The mean extension times and
these 25 products was 65 months, ranging from
the ranges of extension times indicated in the table
15 to 278 months. Other dosage forms of ampi-
represent a combination of the terminated, dor-
cillin, cimetidine HCl, ciprofloxacin, potassium
mant, and active lots. The average extension time
iodide, and povidone-iodine were assigned to other
for these combined lots was 58 months, ranging
from 12 to 137 months. The range of extension
The 23 products assigned to Group 1C (Tab. 4)
times for the two active lots is annotated in the
had only 3–4 lots evaluated. All the 85 lots tested
table. Other dosage forms of ampicillin sodium,
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 95, NO. 7, JULY 2006
Group 1B: Products With No Failures (5–9 Lots Tested)
aSee ‘‘injection-solution’’ dosage form (Group 2).
bSee ‘‘injection-solution’’ dosage form (Group 2).
cSee ‘‘tablet’’ dosage form (Group 1A).
dSee ‘‘tablet’’ dosage form (Group 1A).
eSee ‘‘solution’’ dosage form (Group 4).
chlorpromazine HCl, cimetidine, morphine sul-
annotated in the table. The reasons for denying
fate, and sodium chloride were assigned to other
the extension of the 22 lots was due to a variety of
test failures as indicated in the table. Other dosage
Each of the 13 products assigned to Group 3
forms of atropine sulfate, doxycycline hyclate, and
(Tab. 6) had most lots extended initially (50%
morphine sulfate were assigned to other groups.
occurrence) and none of the extended lots were
Each of the 16 products assigned to Group 4
terminated due to failure (periodic retest). Of the
(Tab. 7) had most lots extended initially (50%
278 lots tested, 256 lots were extended and 22 lots
occurrence) and some of the extended lots were
were denied extension. Of the extended lots, 81 lots
terminated due to failure (periodic retest). Of the
are now dormant and 175 lots are currently active
1675 lots tested, 1402 lots were extended and 273
(primarily 159 lots of doxycycline hyclate tablets).
lots were denied extension. Extension denials were
The average extension for these dormant lots was
due to a variety of test failures as indicated in the
74 months and the average extension for these
table. Of the extended lots, 431 lots eventually
active lots was 30 months. The average extension
failed and were terminated, 519 lots now dormant
time for all of the lots from these 13 products was
and 452 lots are currently active (primarily 119 lots
44 months, ranging from 12 to 216 months. For
of atropine sulfate autoinjectors and 188 lots of
three products, the extension times represent a
pralidoxime chloride autoinjectors). For the termi-
combination of the active and dormant lots. In
nated lots, the amount of shelf life extension before
these cases, the range for the active lots is
the failure ranged from 12 to 266 months with an
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 95, NO. 7, JULY 2006
Group 1C: Products With No Failures (3–4 Lots Tested)
aSee ‘‘tablet’’ dosage form (Group 2).
average of 67 months. Termination was due to a
failures as indicated in the table. The average
variety of test failures as indicated in the table. The
extension for the 16 dormant lots was 33 months.
range of extension times for the active lots is
The average extension time for all of the lots
annotated in the table. The average extension for
(terminated and dormant) from these 10 products
these dormant lots was 81 months and the average
was 38 months, ranging from 14 to 94 months. For
extension for these active lots was 79 months. The
the individual products, the mean extension times
average extension time for all of the lots (termi-
and the ranges of extension times in the table
nated, dormant, and active) from these 16 products
represent a combination of the terminated and
was 76 months, ranging from 12 to 266 months. The
dormant lots. The spray dosage form of diphenhy-
ointment dosage form of povidone-iodine was
dramine HCl was assigned to Group 1A.
Each of the 10 products assigned to Group 5
(Tab. 8) had most of the lots denied initial
extension (50% occurrence) and some of theextended lots were terminated due to failure
(periodic retest). Of the 83 lots tested, 23 lots wereextended and 60 lots were denied extension.
Each product tested was assigned to one of five
Extension denials were due to a variety of test
groups (as listed in Tab. 1) based on an explicit
failures as indicated in the table. Of the extended
classification system. Products with no failures
lots, 7 lots eventually failed and were terminated,
(initial extension failure or termination failure)
16 lots are now dormant, and none of the lots are
were assigned to Group 1. This does not imply
currently active. For the terminated lots, the
that these products will be stable indefinitely.
amount of shelf life extension before the failure
Based on past performance, these products may
ranged from 17 to 94 months with an average of
be considered the best candidates for shelf life
49 months. Termination was due to a variety of test
extension. Other factors, including the number of
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* See See See Active Ac Ac 4-Ep Particula Bactra
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lots tested and the minimum extension time
tested. The combination of lots from atropine
surpassed by all lots tested, need to be considered
sulfate autoinjectors (687 tested), pralidoxime
in evaluating the performance of these products.
chloride autoinjectors (412 tested), and pyridos-
Group 1 was divided into 3 subgroups based on
tigmine bromide tablets (152 tested) represents
the number of lots tested. A greater confidence in
42% of the total lots summarized in this report.
the ability to extend the shelf life was associated
Despite the failures, this group was relatively
with Group 1A (10 lots tested). The most prolific
successful, considering 1404 (84%) of the 1675 lots
performer from this subgroup was ciprofloxacin
tested were initially extended. Diazepam auto-
tablets (242 lots tested with 205 lots still active).
injectors (67 lots tested) had only one lot that failed
Two other top performers from this group were
initial extension and pralidoxime chloride powder
naloxone HCl (all 10 lots extended at least 5 years)
(80 lots tested) had only two lots that failed initial
and halothane (all 12 lots extended over 4 years).
extension. Of the extended pralidoxime chloride
The top performer in Group 1B was potassium
powder lots, only two were terminated, but these
iodide granules with all five lots still active nearly
two lots were extended for more than 8 years.
20 years after the original expiration date.
Other products were successfully extended includ-
In addition, all of the lots of calcium chloride
ing pralidoxime chloride autoinjectors (97% of lots
injection-solution and fentanyl citrate injection-
tested), lactated Ringers injection solution (95%,
solution were extended more than 5 years. All of
59 lots tested), and pyridostigmine bromide tablets
the lots of two products from Group 1C (bupiva-
(93% of lots tested). The product exhibiting the
caine HCl injection-solution and penicillin G
greatest lot-to-lot variability was atropine sulfate
benzathine suspension) were extended more than
autoinjectors. Hundred and ninety two lots (28%)
failed initial extension. The range of extension
Although Group 2 had some lots that encoun-
times for lots of atropine sulfate autoinjectors
tered termination failure, some of these products
exhibiting termination failures was 1–11 years.
could be considered quite reliable. Examples from
For each of the 10 products assigned to Group 5,
this group indicate that if products are stored long
most of the lots could not be extended. Lot-to-lot
enough, failures are bound to occur. Of the products
variability was also evident with this group. Five of
with 10 lots tested, notable examples are listed.
the seven penicillin G procaine powder lots could
All of the cephapirin sodium powder lots (13 tested)
not be extended, while the other 2 lots were
were extended at least 4 years with only one
extended for more than 5 years. Fourteen of 21
termination, occurring at 8 years and all of the
mefloquine HCl tablets lots could not be extended,
pancuronium bromide injection-solution lots (13
1 extended lot was terminated at 17 months, while
tested) were extended at least 4 years with only one
1 lot was extended for more than 7 years. Of the 83
termination, occurring at 7 years. In addition,
lots tested, only 28% could be initially extended.
sulfadiazine silver cream (37 lots tested) had only
All of the products in this group were considered
one termination, occurring after 4 years and
poor candidates and were discontinued from the
dextrose injection-solution (23 lots tested) had four
terminations, but all occurred after 8 years.
termination failures, but for each product one tofour lots failed initial extension, exemplifying lot-
As more lots were tested, the chances that a lot
to-lot variability. In some cases the extension
would fail increased. This was reflected in the
times were quite long. Although two lots of
group classifications. Of the 27 products with 15 or
cefazolin sulfate powder failed initial extension,
more lots tested, 13 products are assigned to Group
the eight remaining lots were extended more than
4 compared to only 5 products assigned to Group
5 years. One lot of spectinomycin sodium suspen-
1A. Sulfadiazine silver, now assigned to Group 2,
sion failed initial extension, but the seven remain-
did not have any failures during the first 11 years
ing lots were extended more than 4 years.
on the program. Up until the termination failure of
The products assigned to Group 4 had some lots
the 27th lot tested, this product was classified as
exhibiting initial extension failure and some lots
Group 1A. Diazepam autoinjectors, now assigned
exhibiting termination failures. The lot-to-lot
to Group 4, did not have an initial extension failure
variability and the need for systematic testing
during the first 6 years on the program. Up until
were most evident with this group. This group
the initial extension failure of the 48th lot tested,
includes products that have been extensively
this product was classified as Group 2. Doxycycline
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 95, NO. 7, JULY 2006
tablets, now assigned to Group 3 did not have an
study could be used to select promising potential
initial extension failure during the first 6 years on
candidates for an extension program.
the program. Up until the initial extension failureof the 13th lot, this product was classified as Group1A. This illustrates that the group classifications
may be dependent on the number of lots tested.This also supports the subclassification of Group
The authors are grateful to Christopher D. Ellison
of the Division of Product Quality Research foreditorial assistance.
The SLEP has been successful in helping to
maintain drug reserves and reducing costs forthe US Military. It is expected that similar
1. Woods M. Drugs may outlast label date. Post-Gazette
programs will be implemented to preserve regio-
National Bureau. May 30, 2005. Available at: http://www.post-gazette.com/pg/05150/512789.stm.
nal and national pharmaceutical stockpiles. One
2. Cohen LP. Many medicines prove potent for years
example is the SNS, formerly the National
past their expiration dates. The Wall Street
Pharmaceutical Stockpile, managed jointly by
the Department of Homeland Security and the
3. Garamone J. Program extends drug shelf-life.
Department of Health and Human Services.10
American Forces Press Service. March 29, 2000
Available at: http://www.defenselink.mil/news/Mar
material stock is rotated and kept within potency
shelf-life limits. The FDA has issued a shelf life
4. American Medical Association. ‘‘Pharmaceutical
extension guidance for federal agencies and state
Expiration Dates’’. Report 1 of the Council on Scien-
and local governments. A specific guidance was
tific Affairs (A-01). July 25, 2001. Available at:
issued by CDER presenting FDA’s recommenda-
http://www.ama-assn.org/meetings/public/annual01/csa_reports.pdf#search ¼ ‘Pharmaceutical%20Expi-
tions on testing to extend the shelf life of stock-
piled potassium iodide.11 This guidance describes
5. Stark G, Fawcett JP, Tucker IG. 1997. A study of the
how to identify laboratories suitable to conduct
stability of some commercial drug dosage forms
the tests, how to notify holders of stockpiled drug
beyond their expiration dates. Pharm J 258:637–640.
products and end users about changes in expira-
6. Regenthal R, Stefanovic D, Albert T, Trauer H,
tion date, and how to distinguish stockpiled
Wolf T. 2002. The pharmacologic stability of 35-
batches with different expiration dates.
year old theophylline. Hum Exp Toxicol 21:343–346.
7. Scholtissek C, Webster RG. 1998. Long-term
stability of the anti-influenza A compounds—amantadine and rimantadine. Antiviral Res 38:
The SLEP data supports the assertion that many
drug products can be extended past the original
8. International Conference on Harmonization: ‘‘Gui-
expiration date, but this additional stability
dance for Industry Q1A(R2) Stability Testing of
period is highly variable. Due to the lot-to-lot
New Drug Substances and Products.’’ Available at:
variability, the stability and quality of extended
http://www.fda.gov/cder/guidance/5635fnl.pdf.
drug products can only be assured by periodic
9. DOD-FDA Shelf Life Extension Program website.
Available at: http://www.usamma.army.mil/html/
testing and systematic evaluation of each lot. The
results of this stability program can only be
10. Strategic National Stockpile website. Available at:
related to products that have been carefully
stored in their original sealed container closures.
11. FDA: ‘‘Guidance for Federal Agencies and State
The class groupings indicate past stability perfor-
and Local Governments Potassium Iodide Tablets
mance and do not guarantee future performance.
Shelf Life Extension.’’ Available at: http://www.
The classification of products presented in this
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 95, NO. 7, JULY 2006

A LINE ON LIFE 11/19/95 The Night Walkers * David A. Gershaw, Ph.D. No, the night walkers are not some leftover from Halloween. The term refers to the Restless Leg Syndrome (RLS) . This sleep disorder is just now gaining acceptance as a psychiatric disorder. Sufferers have pain or strange pulling or crawling sensations in their legs that interfere or prevent them from slee